This invention relates to ruthenium (II) compounds, to their use in medicine, particularly for the treatment and/or prevention of cancer, and to a process for their preparation.
Certain ruthenium (II) complexes have been proposed for use in treating cancer. For example, U.S. Pat. No. 4,980,473 discloses 1,10-phenanthroline complexes of ruthenium (II) and cobalt (III) which are said to be useful for the treatment of tumour cells in a subject.
Some other ruthenium (II) and ruthenium (III) complexes which have been shown to exhibit antitumour activity are mentioned in Guo et al, Inorganica Chimica Acta, 273 (1998), 1-7, specifically trans-[RuCl2(DMSO)4], trans-[RuCl2(imidazole)2]- and trans-[RuCl4(indazole)2]. Guo et al discloses that the most interesting feature of these complexes is their anti-metastatic activity. Clarke et at have reviewed the anticancer and in particular the antimetastatic activity of ruthenium complexes: Chem. Rev. 1999, 99, 2511-2533. Also, Sava has reveiwed the antimetastatic activity in xe2x80x9cMetal Compounds in Cancer Therapyxe2x80x9d Ed by S P Fricker, Chapman and Hall, London 1994, p. 65-91.
Dale et al, Anti-Cancer Drug Design (1992), 7, 3-14, describes a metronidazole complex of ruthenium (II) ie, [(xcex76-C6H6)RuCl2(metronidazole)] and its effect on DNA and on E. coli growth rates. Metronidazole sensitises hypoxic tumour cells to radiation and appears to be an essential element of the complexes of Dale et al. There is no indication in Dale et al that the complexes would be at all effective in the absence of the metronidazole ligand.
Krxc3xa4mer et al, Chem Eur J., 1996, 2, No. 12, p. 1518-1526 discloses half sandwich complexes of ruthenium with amino esters.
There exists a need for novel anti-cancer compounds which can be used as alternatives to the compounds which are currently available.
The present invention provides a novel class of ruthenium (II) complexes having anti-tumour activity.
According to the present invention there is provided a ruthenium (II) compound of formula (I): 
wherein:
R1, R2, R3, R4, R5 and R6 independently represent H, alkyl, xe2x80x94CO2Rxe2x80x2, aryl or alkylaryl, which latter two groups are optionally substituted on the aromatic ring;
Rxe2x80x2 represents alkyl, aryl or alkaryl;
X is halo, H2O, (Rxe2x80x2)(Rxe2x80x3)SO, Rxe2x80x2CO2xe2x80x94 or (Rxe2x80x2)(Rxe2x80x3)Cxe2x95x90O, where Rxe2x80x3 represents alkyl, aryl or alkaryl;
Y is a counterion;
m is 0 or 1;
q is 1, 2or 3;
Cxe2x80x2 is C1 to C12 alkylene, optionally substituted in or on the alkylene chain, bound to two A groups;
p is 0 or 1 and r is 1 when p is 0 and r is 2 when p is 1; and
A and B are: each independently N-donor nitrile ligands; or B is halo and A is an N-donor pyridine ligand, optionally substituted at one or more of the carbon atoms of the pyridine ring; or p is 0, A is NR7R8 and B is NR9R10, wherein R7, R8, R9 and R10 independently represent H or alkyl, and A and B are linked by an alkylene chain, optionally substituted in or on the alkylene chain; or p is 1, A is NR7 and B is NR9R10, wherein R7, R9 and R10 are as previously defined, and A and B are linked by an alkylene chain, optionally substituted.
The compounds of the invention may be in the form of solvates and/or prodrugs. Prodrugs are variants of the compounds of the invention which can be converted to compounds of formula (I) in vivo.
The compounds of formula (I) may have one or more chiral centres. When the compounds of formula (I) have one or more chiral centres, they may be in the form of one enantiomer, may be enriched in one enantiomer or may be a racemic mixture.
The term xe2x80x9calkylxe2x80x9d as used herein includes C1 to C6 alkyl groups which may be branched or unbranched and may be open chain or, when they are C3 to C6 groups, cyclic. Unbranched open chain alkyl groups include, for example, methyl, ethyl, propyl, butyl, pentyl and hexyl. Branched open chain alkyl groups include, for example, 2-propyl, 2-butyl and 2-(2-methyl)propyl. Cyclic groups include cyclopropyl; cyclobutyl, cyclopentyl and cyclohexyl. The alkyl groups in the compounds of the invention may optionally be substituted. Substituents include one or more further alkyl groups and/or one or more further substituents, such as, for example, cyano, nitro, hydroxyl, haloalkyl, xe2x80x94CO2alkyl, halo, thiol (SH), thioether (eg, S-alkyl) and sulfonate. The term xe2x80x9calkylenexe2x80x9d is defined similarly to the definition of the term xe2x80x9calkylxe2x80x9d but includes C2 to C12 groups and is a divalent species with radicals separated by two or more (eg, from two to twelve) carbon atoms linked in a chain. Preferably, the alkylene groups are straight chain groups. Alkylene groups are optionally substituted in the alkylene chain, preferably with one or more phenylene (eg, 1,4phenylene) and/or xe2x80x94CONR1axe2x80x94 groups and/or xe2x80x94NR2axe2x80x94 groups, where R1a and R2a independently represent H, alkyl, aryl or alkaryl. Preferably, R1a and R2a are H or C1 to C3 alkyl.
The term xe2x80x9carylxe2x80x9d as used herein includes aromatic carbocyclic rings such as phenyl and naphthyl and heterocyclic rings such as pyridyl, imidazolyl, pyrrolyl and furanyl. Aryl groups may optionally be substituted with one or more substituents including, for example, alkyl, cyano, nitro, hydroxyl, haloalkyl, xe2x80x94CO2alkyl, halo, thiol (SH), thioether (eg, S-alkyl) and sulfonate.
The term xe2x80x9calkarylxe2x80x9d means alkyl substituted with aryl eg, benzyl.
The term xe2x80x9chaloxe2x80x9d means a halogen radical selected from fluoro, chloro, bromo and iodo.
The term xe2x80x9chaloalkylxe2x80x9d means alkyl substituted with one or more halo groups eg, trifluoromethyl.
In the compounds of formula (I), R1, R2, R3, R4, R5 and R6 may represent H. Alternatively, R1 may be 2-propyl and R4 may be methyl, with R2, R3, R5 and R6 all representing hydrogen. As a further alternative, R1 may be phenyl, with R2, R3, R4, R5 and R6 all representing hydrogen. In a yet further alternative, R1 may be xe2x80x94CO2Rxe2x80x2, such as xe2x80x94CO2CH3 for example, with R2, R3, R4, R5 and R6 all representing hydrogen.
In one aspect, A and B in the compounds of formula (I) both represent R11xe2x80x94CN. R11 is alkyl, preferably C1 to C3 alkyl, more preferably methyl.
In another aspect, one of A and B in the compounds of formula (I) represents a 4-substituted pyridine and the other represents halo. The pyridine may be substituted at the 4-position by, for example, groups including nitro, cyano and C(O)NR12R13 wherein R12 and R13 are independently selected from H and alkyl (eg, C1 to C6 alkyl). The group at the 4-position of the pyridine ring is preferably an electron withdrawing group.
In a further aspect, A and B may together represent NR7R8xe2x80x94(CR12R13)nxe2x80x94NR9R10, wherein R12 and R13 are independently H or allyl or R12 and R13 groups, on the same carbon atom or on neighbouring carbon atoms, are linked to form a carbocylic ring and n is an integer from 1 to 4. Preferably, R12 and R13 are both hydrogen and n is 2 or 3, more preferably 2. R7, R8, R9 and R10 are preferably H or methyl and, more preferably, all of R7, R8, R9 and R10 are H.
When R8 is present in A, then p is 0. When R8 is absent, then p is 1.
In a further aspect of the invention, R8 is absent from A, p is 1 and Cxe2x80x2 is C4 to C10 straight chain alkylene (eg, hexylene). Compounds according to this aspect of the invention are so-called dinuclear complexes comprising two ruthenium atoms per complex.
Other examples of dinuclear complexes of the invention are those in which is A and B together represent: 
wherein each nxe2x80x2, nxe2x80x3, xxe2x80x2, xxe2x80x3 and yxe2x80x2 independently represents an integer from 1 to 12, preferably 1 to 6.
Yqxe2x88x92 in compounds of formula (I) is a counterion and is only present in the compound when the complex containing the metal ion is charged. Yqxe2x88x92 is preferably a non-nucleophilic anion such as PF6xe2x88x92, for example.
Rxe2x80x2 and Rxe2x80x3 are preferably alkyl. Most preferably, both Rxe2x80x2 and Rxe2x80x3 are methyl.
Compounds of formula (I) may be used in medicine. In particular, compounds of formula (I) may be used to treat and/or prevent cancer.
Therefore, the present invention also provides the use of a compound of the invention (ie, a compound of formula (I)) in the manufacture of a medicament for the treatment and/or prevention of cancer.
Further provided by the invention is a method of treating and/or preventing cancer which comprises administering to a subject a therapeutically effective amount of a compound of the invention.
The compounds of the invention may be used directly against a tumour. Alternatively or additionally, the compounds may be used to prevent or inhibit metastasis and/or to kill secondary tumours. It will be understood that the prevention or inhibition of metastasis is encompassed by the term xe2x80x9cpreventing cancerxe2x80x9d, as used herein.
The invention also provides a pharmaceutical composition comprising one or more compounds of the invention together with one or more pharmaceutically acceptable excipients. Suitable excipients include diluents and/or carriers.
The compounds of the invention may be administered by a number of routes including, for example, orally, parenterally (eg, intramuscularly, intravenously or subcutaneously), topically, nasally or via slow releasing microcarriers. Thus, suitable excipients for use in the pharmaceutical compositions of the invention include saline, sterile water, creams, ointments, solutions, gels, pastes, emulsions, lotions, oils, solid carriers and aerosols.
The compositions of the invention may be formulated in unit or subunit dosage form including, for example, tablets, capsules and lozenges and containers containing the composition in a form suitable for parenteral administration.
The specific dosage level of the compounds and compositions of the invention will depend upon a number of factors, including the biological activity of the specific compound used and the age, body weight and sex of the subject. It will be appreciated that the subject may be a human or a mammalian animal.
The compounds and compositions of the invention can be administered alone or in combination with other compounds. The other compounds may have a biological activity which complements the activity of the compounds of the invention eg, by enhancing its effect in killing tumours or by reducing any side-effects associated with the compounds of the invention.
The present invention also provides a process for preparing the compounds of the invention which comprises the reaction of a compound of formula [(xcex76-C6(R1)(R2)(R3)(R4)(R5)(R6))RuX2], which may be in the form of a monomer or a dimer, with A and B, optionally in the presence of Yqxe2x88x92, in a suitable solvent for the reaction, wherein R1, R2, R3, R4, R5, R6, X, A, B and Y are as defined above for the compounds of the invention.
Suitable compounds of formula [(xcex76-C6(R1)(R2)(R3)(R4)(R5)(R6))RuX2] for use as starting materials (starting ruthenium complexes) in the process of the invention include [(xcex76-C6H6)RuCl2]2, [(xcex76-C6H6)RuBr2]2, [(xcex76-C6H6)RuI2]2, [(xcex76-p-cymene)RuCl2]2, [(xcex76-p-cymene)RuBr2]2 and [(xcex76-p-cymene)RuI2]2 which can be prepared by known methods eg Bennett et al, J. Chem. Soc. Dalton Trans., 1974, 233.
When A and B in the compounds of the invention are R11xe2x80x94CN, the solvent for the reaction may be R11xe2x80x94CN itself. Preferred reaction conditions include stirring the starting ruthenium complex, as described above, in R11xe2x80x94CN as solvent at room temperature until a sufficient amount of product is formed. The reaction mixture comprises a source of Yqxe2x88x92, such as a compound of formula (NH4+)Yqxe2x88x92 eg, NH4PF6.
Compounds of formula (I) in which A and B represent, together, NR7R8xe2x80x94(CR12R13)nxe2x80x94NR9R10 or NR9R10xe2x80x94(CR12R13)nxe2x80x94NR7xe2x80x94Cxe2x80x2xe2x80x94NR7xe2x80x94(CR12R13)nxe2x80x94NR9R10 can be produced, according to the process of the invention, by stirring the starting ruthenium complex in the presence of a slight excess of NR7R8xe2x80x94(CR12R13)nxe2x80x94NR9R10 or an equimolar amount of NR9R10xe2x80x94(CR12R13)nxe2x80x94NR7xe2x80x94Cxe2x80x2NR7xe2x80x94(CR12R13)nxe2x80x94NR9R10, respectively, in a suitable solvent, preferably an alcoholic solvent such as methanol. The reaction may be carried out at room temperature or at elevated temperature (eg, 30xc2x0 C. to 90xc2x0 C.) until a sufficient amount of product is formed; optionally after cooling the reaction mixture. The reaction mixture comprises a source of Yqxe2x88x92, such as a compound of formula (NH4+)Yqxe2x88x92 eg, NH4PF6.
Compounds of formula (I) in which A or B is an N-donor pyridine ligand may be obtained, according to the process of the invention, by heating a mixture of the starting ruthenium complex and excess pyridine compound (such as a 1.5- to 3- fold molar excess) in a suitable solvent such as benzene until a sufficient amount of product is formed. The reaction may be carried out under reflux conditions.
The precipitate which is formed in the process of the invention comprises or consists of the compound of the invention. The compound of the invention may be isolated from the reaction mixture by separating the precipitate from the liquid phase (eg, by filtration) and then removing the solvent from the precipitate (eg, under reduced pressure). The solid thus formed, which comprises or consists of the compound of the invention may, optionally, be purified eg, by recrystallisation from a suitable solvent (including, for certain compounds of the invention, acetonitrile or acetonitrile/ether (where A and B are R11xe2x80x94CN and R11 is methyl) and methanol/ether).
The following non-limiting examples illustrate the present invention.